Immunotherapy Approaches in HPV-Associated Head and Neck Cancer

Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.

1168 Radiotherapy Dose for HPV Driven Oropharyngeal Cancer: What Is Enough?

Aim Squamous cell carcinoma of the oropharynx is associated with high-risk Human Papilloma Virus (HPV) infection. HPV positive oropharyngeal cancer is often more radiosensitive and first line treatment includes either radiotherapy or surgical resection. Trials are ongoing to establish situations in which radiation doses can be reduced with the aim of reducing late tissue toxicity (“de-escalation trials”) . We report a case in which a patient failed to complete his prescribed radiotherapy treatment, describe his clinical outcomes and the potential questions this situation raises. Method In 2009 a male patient presented with a right T2N0MO P16 positive tonsillar squamous cell carcinoma. He was scheduled to complete a course of chemoradiotherapy. However, he was only able to complete a third of the radiotherapy course. Due to unresolved symptoms, he underwent a right transoral laser extended tonsillectomy, however this showed only fibrous tissue. Results Despite not completing the radiotherapy course he has not experienced local recurrence of the tonsillar OPSCC 11 years post initial treatment. Conclusions This case illustrates that some patients with HPV driven oropharyngeal cancer can have a clinically significant tumour response to markedly lower doses of radiotherapy than is currently recommended. Further randomized controlled trials are required to establish the optimum dose in the management of HPV driven oropharyngeal squamous cell cancer.

Caracterização socioepidemiológica da população acometida pelo HPV e as dificuldades no manejo da doença / Socio-epidemiological characterization of the population affected by HPV and the difficulties in managing the disease

Introdução: O papiloma vírus humano, ou HPV, é um vírus que infecta pele ou mucosa, transmitido por meio do contato direto, ou indireto com a área afetada. Esta infecção em sua maioria regride, porém, em seu pequeno número de casos, onde persiste, podem progredir para o câncer de colo do útero. O câncer de colo uterino é prevenível com associação a vacina e a realização de exames preventivos de rotina que detectam a lesão precursora. Objetivo: Realizar a análise socioepidemiológica do HPV, avaliar o perfil da população acometida pela doença e identificar os impactos no manejo da doença para entender como reduzir os números de casos. Materiais e métodos: O presente estudo se deu de modo descritivo realizado através de consultas de dados de bases científicas. Resultados: A técnica de citologia oncótica, como forma de rastreio do HPV e prevenção ao câncer de colo do útero, apresentou diversas limitações, como baixa a moderada sensibilidade, baixa reprodutibilidade e grande número de falso-negativos. O rastreio do HPV por PCR em tempo real apresentou-se como o método mais eficaz no diagnóstico do HPV por apresentar maior sensibilidade e eficiência para o rastreio. A educação sexual mostrou-se indispensável tanto para informações a respeito da doença, quanto para a prevenção. Discussão: São necessários investimentos no desenvolvimento de práticas para a promoção da saúde, além da campanha realizada atualmente para vacinação contra HPV, é preciso associar a campanhas de uso de preservativo e campanhas de incentivo a realização de exames de rastreamento, além da inclusão de educação sexual em escolas e abordagem pela família. Assim é possível conscientizar a população, refletindo diretamente na redução da contaminação. Conclusão: O teste de rastreamento disponibilizado na rede pública e o acesso à informação sobre medidas de prevenção se mostraram como fatores que dificultam o manejo do HPV. Ainda com todas as informações levantadas, são necessárias mais avaliações para que assim projetos mais efetivos sejam implementados para o controle do HPV.Palavras chave: HPV, Câncer de colo do útero, Teste de Papanicolaou, HPV, PCR, PapanicolaouABSTRACTIntroduction: Human papilloma virus, or HPV, is a virus that infects the skin or mucosa, transmitted through direct or indirect contact with the affected area. This infection mostly regresses, however, in its small number of cases, where it persists, it can progress to cervical cancer in women. Cervical cancer is preventable in combination with the vaccine and routine preventive examinations that detect the precursor lesion. Objective: Perform the socio-epidemiological analysis of HPV, evaluate the profile of the population affected by the disease and identify the impacts on the management of the disease for understand how to reduce number of cases. Materials and methods: The present study was carried out in a descriptive way, carried out through scientific data consultations. Results: The oncotic cytology technique, as a way of screening HPV and preventing cervical cancer, presented several limitations, such as low to moderate sensitivity, low reproducibility and a large number of false negatives. HPV screening by real-time PCR was shown to be the most effective method for diagnosing HPV because it has greater sensitivity and efficiency for screening. Sex education proved to be indispensable both for information about the disease and for prevention. Discussion: Investments are needed in the development of practices for health promotion, in addition to the campaign currently carried out for vaccination against HPV, it is necessary to associate it with campaigns of condom use and campaigns to encourage the performance of screening tests, in addition to the inclusion of sexual education in schools and family approach. Thus it is possible to raise awareness among the population, directly reflecting on the reduction of contamination. Conclusion: The screening test made available on the public network and access to information on preventive measures proved to be factors that hinder the management of HPV. Even with all the information collected, more evaluations are necessary so that more effective projects are implemented for the control of HPV.Keywords: HVP, Cervical cancer, HPV Test, PCR, PAP smear

Human Papillomavirus Associated Oropharyngeal Carcinoma-Diagnosis and Management

Head and neck squamous cell carcinomas arise from the mucosa of the upper aerodigestive tract and is often driven by risk factors like tobacco and alcohol consumption. Most of the time patients present with locally advanced stages and the outcome is poor, despite recent advances in multi-modality treatment. The epidemiology of the disease has changed over the last decade with the introduction of a separate clinical entity; Human Papillomavirus (HPV) associated head and neck cancer. The tumorigenesis is different from that of tobacco and alcohol-driven malignancies. These tumors have a better response to treatment owing to their inherent genetic makeup and carry an excellent prognosis. The current school of thought is to reduce the long-term morbidities associated with various treatment modalities, as these patients tend to survive longer. The best management of HPV-associated oropharyngeal cancer is under active investigation.

Human Papillomavirus: Pathogenesis and Correction of Immune Disturbances

Objective of the Review: To present current information on the epidemiology and pathogenesis of cervical conditions associated with human papillomavirus (HPV), and of associated immunodysfunctions, based on the analysis of data from Pubmed, Google Scholar, Embase search systems. Key Points. Clinical manifestations of HPV include neoplastic processes in cervix, vulva, vagina, and rectum. The primary management of HPV-associated cervical disorders is surgical resection of affected tissue; however, the approach is not always efficient, since where surgical resection is used alone, the recurrence rate is 20–30%; the virus persists not only on treated areas, but also recorded de novo. Pathogenic peculiarities of HPV-associated conditions are a result of evolutionary aspects of developments and interactions in the “HPV — microorganism” system; they are dependent on antibacterial potential, activity of Toll-like receptors 4, 9, Th1/Th2 balance, the balance between cytokines expressed by Т-helper subpopulations and an immunocompetence shift towards Th2. Conclusion. Immunomax, an acidic plant peptidoglycane recognisable by Toll-like receptors of cells in charge of immune surveillance in the body, activates antiviral immunity in HPV infection. Keywords: human papillomavirus, immunity, neoplastic cervical processes, Toll-like receptors

G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer

Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant cancer-related genetic and epigenetic modifications. We analyzed the methylation status of 24 G protein-coupled receptor (GPCR) genes in verification (85 OPC primary samples) and validation (8 OPC ctDNA samples) studies using quantitative methylation-specific polymerase chain reaction (Q-MSP). The Q-MSP-based verification study with 85 OPC primary samples revealed the GPCR genes that were significantly associated with recurrence in high methylation groups (≥14 methylated genes) with OPC and HPV-associated OPC (p < 0.001). In the Kaplan–Meier estimate and multivariate Cox proportional hazard analyses, 13 GPCR genes were significantly related to increased recurrence in the methylation group. Furthermore, the validation study on ctDNA showed that three of these genes (Prostaglandin D2 receptor 1: PTGDR1, Prostaglandin D2 receptor 2: PTGDR2, and Prostaglandin I2 Receptor: PTGIR) had a prediction performance as emerging biomarkers. We characterized the relationship between the methylation status of GPCR genes and outcomes in HPV-associated OPC. Our results highlight the potential utility of ctDNA methylation-based detection for the clinical management of HPV-associated OPC.

Management of HPV-Related Squamous Cell Carcinoma of the Head and Neck: Pitfalls and Caveat

Head and neck squamous cell carcinomas (HNSCCs) are a very heterogeneous group of malignancies arising from the upper aerodigestive tract. They show different clinical behaviors depending on their origin site and genetics. Several data support the existence of at least two genetically different types of HNSCC, one virus-related and the other alcohol and/or tobacco and oral trauma-related, which show both clinical and biological opposite features. In fact, human papillomavirus (HPV)-related HNSCCs, which are mainly located in the oropharynx, are characterized by better prognosis and response to therapies when compared to HPV-negative HNSCCs. Interestingly, virus-related HNSCC has shown a better response to conservative (nonsurgical) treatments and immunotherapy, opening questions about the possibility to perform a pretherapy assessment which could totally guide the treatment strategy. In this review, we summarize molecular differences and similarities between HPV-positive and HPV-negative HNSCC, highlighting their impact on clinical behavior and on therapeutic strategies.